Increased exercise tolerance in humanized G6PD-deficient mice
Glucose-6-phosphate dehydrogenase (G6PD) deficiency affects 500 million people globally, affecting red blood cell (RBC) antioxidant pathways and increasing susceptibility to hemolysis under oxidative stress. Despite the systemic generation of reactive oxygen species during exercise, the effects of exercise on individuals with G6PD deficiency remain poorly understood This study used humanized mouse models expressing the G6PD Mediterranean variant (S188F, with 10% enzymatic activity) to investigate exercise performance and molecular outcomes. Surprisingly, despite decreased enzyme activity, G6PD-deficient mice have faster critical speed than mice expressing human canonical G6PD. After exercise, deficient mice did not exhibit differences in RBC morphology or hemolysis, but had improved cardiac function, including cardiac output, stroke volume, sarcomere length, and mitochondrial content. Proteomics analyses of cardiac and skeletal muscles (gastrocnemius, soleus) from G6PD-deficient compared with sufficient mice revealed improvements in mitochondrial function and increased protein turnover via ubiquitination, especially for mitochondrial and structural myofibrillar proteins. Mass spectrometry-based metabolomics revealed alterations in energy metabolism and fatty acid oxidation. These findings challenge the traditional assumptions regarding hemolytic risk during exercise in G6PD deficiency, suggesting a potential metabolic advantage in exercise performance for individuals carrying noncanonical G6PD variants.
Authors
- Karolina H. Dziewulska (ORCID: https://orcid.org/0000-0001-8379-2004)
- Christina Lisk (ORCID: https://orcid.org/0000-0001-6217-4063)
- Eric J. Earley (ORCID: https://orcid.org/0000-0001-6576-1319)
- Julie A. Reisz (ORCID: https://orcid.org/0000-0002-7296-4963)
- Francesca Cendali (ORCID: https://orcid.org/0000-0002-8874-2150)
- David Irwin (ORCID: https://orcid.org/0000-0002-1743-8266)
- Ian S. LaCroix (ORCID: https://orcid.org/0000-0002-4859-7024)
- Grier P. Page (ORCID: https://orcid.org/0000-0003-2582-3786)
- James C. Zimring (ORCID: https://orcid.org/0000-0002-1063-4010)
- Travis G. Nemkov (ORCID: https://orcid.org/0000-0001-8566-7119)
- Angelo D’Alessandro (ORCID: https://orcid.org/0000-0002-2258-6490)
- Philip J. Norris (ORCID: https://orcid.org/0000-0003-0526-2088)
- Ariel Hay (ORCID: https://orcid.org/0000-0002-9003-6415)
- Michael Paul Busch (ORCID: https://orcid.org/0000-0002-1446-125X)
- Daniel Stephenson (ORCID: https://orcid.org/0000-0002-5698-3400)
- Eric P. Wartchow (ORCID: https://orcid.org/0000-0002-6135-270X)
- Kirk C. Hansen (ORCID: https://orcid.org/0000-0001-5054-838X)
- Monika Dzieciątkowska (ORCID: https://orcid.org/0000-0002-9947-2520)
- Paul W. Buehler (ORCID: https://orcid.org/0000-0003-0687-3008)
- Xutao Deng (ORCID: https://orcid.org/0000-0002-7372-3758)
- Julie W. Harral
- Anza Darehshouri (ORCID: https://orcid.org/0000-0001-9125-0213)
Institutions
- University of Maryland, Baltimore (US)
- University of Colorado Hospital (US)
- RTI International (US)
- Pacific Research Institute (US)
- University of Colorado Health (US)
- Children's Hospital Colorado (US)
- Vitalant (US)
- Smith-Kettlewell Eye Research Institute (US)
- University of Virginia (US)
- University of Colorado Anschutz Medical Campus (US)
- University of Colorado Denver (US)
Publication Details
- Journal
- Blood Advances
- Published
- 2024-11-08
- DOI
- https://doi.org/10.1182/bloodadvances.2024013968
- Citations
- 5
- Primary Topic
- Neonatal Health and Biochemistry
- Type
- article
- Field-Weighted Citation Impact
- 5.55
Funders
- National Heart, Lung, and Blood Institute